Blog of the Society for Menstrual Cycle Research

The Huffington Post published a story last week titled “Last Menstrual Cycle Could Be Predicted With New Model”. The story stated that a research study had just been published about a new method for predicting the end of menstruation in which researchers developed a formula for using the levels of two hormones, estradiol and follicle stimulating hormone (abbreviated FSH), to make this estimate. This “new method for predicting a woman’s last menstrual cycle could have broader implications for menopausal women’s health”. Since “in the year leading up to the final menstrual period, women are met with faster bone loss and a greater risk of heart disease”, if the end of menstruation could be predicted, medical monitoring and interventions would become possibilities. The research was also reported as news on the medical website Medscape.

Research results are often reported as news stories, as though these results are facts. However, “dog bites man” and “man bites dog” are facts, but research results are not facts in the same way. They are “evidence” that most often must be evaluated, understood, and put into the context of many other studies. There could very well be disagreement about whether a study’s methods really did accurately make a point, or whether the conclusions the researchers drew from their work were justified. Sadly, it happens all too often that research does not make the point that the headlines claim.

Photo by clarita // morgueFile

Here, we have a study by a respected researcher at a major institution, UCLA, funded by a grant from the National Institutes of Health and other prestigious grantors. However, we do not have the information with which to understand what the researchers actually did. UCLA issued a press release which states that the study “suggests” a way to predict the final period. The Medscape article states that “A new model MAY [my emphasis] help physicians determine how far a woman is from her final menstrual period”.

Suggests? May? I have no idea what this means. As a researcher, I want to look at the published article to see what was actually done. However, the publisher does not make a free copy of the article available. Anyone who wants to look at the published article—a researcher or an informed consumer—would need to pay the publisher $37.00 to access this 20-page article for one day. Predicting the last menstrual period from hormone levels, which is what is claimed, is something other researchers have tried but failed to do, so how these researchers worked with the difficult problems is an important question.

Assume for a moment that the model was a big success, and it did predict the last menstrual period. The idea that this has important implications for women’s health is stated as though it were another fact. However, this is not a fact; this is a complicated and controversial area. Bone density does decrease in the years surrounding menopause, but professionals disagree about how big an effect this has on bone disease. For example, current guidelines recommend testing bone density beginning at age 65, 15 years after the average age of menopause, because this is when the fracture rate has significantly increased. Heart disease risk factors may increase on average in the years surrounding menopause, but professionals disagree about whether menopause is important compared with other factors associated with aging.

Assume for a moment that bone disease really is an important negative health consequence of menopause. Whether interventions would be found that must be started in the year or two before menopause is another speculation. Such interventions might be found or might not. Predicting the last menstrual period, even if the claim is valid that a method to do so has been found, is a long way from preventing disease.

The medical satirist Andrew Vickers wrote an article called “News On Cancer Drug Fails to Raise False Hopes”, which begins: “A recent article on a novel cancer therapy has rocked the newspaper industry by giving a balanced and cautious review of an early-phase trial”. Satirists make extreme statements to make a point. Media reports are often written to sound definite and to portray a study as really important. A cautious approach to medical news is to withhold judgment unless the methodology of the study is clear and the context of the study is understood.

On February 26, 2013, the Food and Drug Administration issued a news release saying that it had approved a medication called Osphena to treat a problem called postmenopausal dyspareunia (pain during sexual intercourse associated with changes in the vagina after menopause). The medical website Medscape reported that the news release had been issued. How to read these announcements? It seems as though FDA approval should be enough to know that a medication is safe and effective. However, what are some guidelines in reading and evaluating this announcement?

This can result in pain during intercourse, feelings of burning or soreness, inflammation, and irritation.

Andreyeva by Ilya Repin // Public Domain via Wikimedia Commons

There are a variety of solutions for dealing with this. Regular sexual stimulation (intercourse, masturbation) is recommended to keep vaginal tissues healthy. Water-based lubricants can help reduce discomfort during intercourse. Expanded views of sexual pleasure that don’t include intercourse might work around the problem. Leaving enough time to become aroused during intercourse (extended foreplay), communication between partners about when sex is painful and when not, can also help. Herbs like dong quai and black cohosh are recommended, especially by complementary/alternative practitioners, although the herbs lack a research base. A low-dose estrogen applied to the vaginal area (as a cream, tablet, etc.), is effective. Local application minimizes estrogen being absorbed into the bloodstream, traveling through the body, and having effects, some of them potentially negative, distant to the vagina. There is, however, controversy about some estrogen being absorbed.

Now, to the FDA announcement: The FDA requires proof of a medication’s safety and effectiveness before it is approved. According to the news release: “Osphena’s safety and effectiveness were established in three clinical studies of 1,889 postmenopausal women with symptoms of vulvar and vaginal atrophy. Women were randomly assigned to receive Osphena or a placebo. After 12 weeks of treatment, results from the first two trials showed a statistically significant improvement of dyspareunia in Osphena-treated women compared with women receiving placebo. Results from the third study support Osphena’s long-term safety in treating dyspareunia.”

Notice, first, that the drug’s effectiveness was tested for 12 weeks. This is not an unusual amount of time for such a study, but it is not very much time. Notice also that women treated with Osphena had a “statistically significant” improvement. As I discussed in a previous post, “statistically significant” means “unlikely to have occurred by chance.” In other words, there was evidence that Osphena really did have an effect, but we don’t know how big an effect—it might be very large or very small.

Safety was established by studying the experiences of women for one year: however, one year is not a long time for side effects to develop. Osphena is a systemic medication. That means it is not applied locally in the vaginal area, it is ingested as a pill so that it travels to all parts of the body in the bloodstream. It is a selective estrogen-receptor modulator, or SERM. SERMs act like estrogen in some places in the body while not in others. The idea is that a SERM like Osphena would act like estrogen in keeping vaginal cells healthy while not acting like estrogen to increase health risks like certain cancers. However, more time than a year might be needed for health problems to show up. Indeed, the FDA news release stated that “Osphena is being approved with a boxed warning alerting women and health care professionals that the drug, which acts like estrogen on vaginal tissues, has shown it can stimulate the lining of the uterus (endometrium) and cause it to thicken…. Women should see their health care professional if they experience any unusual bleeding as it may be a sign of endometrial cancer or a condition that can lead to it.” The FDA announcement also stated that “Common side effects reported during clinical trials included hot flush/flashes, vaginal discharge, muscle spasms, genital discharge and excessive sweating” and that Osphena should be prescribed for the “shortest duration consistent with treatment goals and risks for the individual woman.” Continue reading...

It turns out that phthalates – chemicals found in cosmetics, hairspray, packaged food, household cleaners, and other common plastic items – are causing early menopause. At least according to one new study that is getting a lot of hype in the past week or two. A team of researchers from Washington University in St. Louis, MO, studied phthalate levels in blood and urine for over 5,000 women, and those women with the highest levels of pthalates apparently went into menopause an average of at least two years before others.

This study is definitely making news. British news sources are reporting on this study as much as U.S. news sources. Women’s reactions to online news stories about this study are mixed. Women hearing about this study are quick to comment online, saying either (1) how quickly they’ll be running out to buy more makeup (to launch themselves into menopause) or (2) discontinuing their use of makeup (to ward against the effects of pthalates). What I find interesting is how divided women are about whether early menopause is good. Reactions to reports on this study definitely show attitudinal differences among women in that women do not think uniformly about menopause or about the importance of using cosmetics. Women are not thinking uniformly about how damaging phthalates are to our bodies either.

Of course, by all news reports of this study, phthalates also cause cancer, diabetes, and even feminization of boys (really?), so even if you think early menopause is a good thing you might want to hold off on consuming more phthalates.

What this study (and people’s belief in the study) also reiterates is the fact that our bodies are affected by what we eat, use, and do, as well as what we come into contact with, where we live, etc. Some of the articles reporting on this study focus in on the natural, healthy choices we can make when picking beauty products, household cleaners, prepared food, and other common household items. Who knew there was vegan makeup, for instance? This is all worth a second thought. Sure, we might all want to be done with menstruation sooner than later but phthalate-induced menopause should probably not be our goal.

Many of us do our own health research, either because we have a specific question or simply to keep up with the news. If we don’t read the original scientific articles, we rely on experts to provide summaries in newspapers, magazines, or on a variety of websites. It seems as though by choosing sources judiciously we should be able to count on finding information that is accurate. However, relying on authority, whether this authority derives from a writer having scientific or medical training, or the writer being a professional journalist, or some other reason, is not enough.

I thought about this recently when I saw an article on Medscape, a website for health professionals, especially physicians, called “Early menopause doubles CVD risk regardless of race.” A summary of a new journal article, it was highlighted on the Medscape home page for many days. It began: “Women who experience early menopause–before their 46th birthday–are twice as likely to suffer from coronary heart disease and stroke as women who don’t enter menopause prematurely, and this finding is independent of traditional risk factors.” Johns Hopkins University, where one of the authors is employed, issued a press release entitled “Early Menopause Associated With Increased Risk Of Heart Disease, Stroke” which also begins: “Women who go into early menopause are twice as likely to suffer from coronary heart disease and stroke, new Johns Hopkins-led research suggests.” Similar articles appeared in Medline+ (a National Institutes of Health and National Library of Medicine website), a Blue Cross Blue Shield healthcare news website, and many print newspapers.

So, what was in the original scientific article? The article was published in Menopause, which, like many journals, does not post its articles free online for non-subscribers. Many academic libraries do not carry this journal. However, if a reader does get the original article, these are some of the details: The women in this research were studied for a number of years. The researchers collected information about many predictors of circulatory problems (smoking, diabetes, etc.). The women were also asked at what age they had reached menopause. If this was when they were younger than 46, they were classified as having an “early menopause” whether menopause was caused by surgery (ovaries removed) or occurred naturally. The researchers looked at whether the women developed heart problems or strokes, and created mathematical models to study which predictors of these problems were important.

Twice the number of women with “early menopause” had heart problems compared with women who reached menopause later. This is what is called “relative risk.” The “absolute risk” numbers were: 3% of the women with early menopause had heart problems compared with 1.4% of those who did not; for stroke, the numbers were 2.6% vs. 1%. This is still a difference, but not as dramatic as a twofold increase. In addition, the way the strength of the association was mathematically computed was to first predict heart problems and stroke with more usual predictors: age, risk factors like diabetes. The difference in risk due to menopause was in the uncertainty left after all these other factors had already been taken into account. Further, we don’t know whether the “early menopause” group had other associated characteristics leading to a health difference—if they were unhealthy in other ways. The authors, for example, state that if a woman had a family history of heart problems, and if this was mathematically taken into account before looking at menopause, then early menopause was no longer a predictor of her having a problem. In accounting for results, the article cannot distinguish between surgical and natural menopause, which differ in many ways.

It is true that, in the media accounts of this research, if a reader reads the entire article, qualifiers do appear embedded in the article in some of the sources. Some do say that the number of women in the study who developed heart problems or strokes was small; that this was a correlation, not a cause-and-effect association; or that when family history of cardiovascular disease was taken into account the relationship disappeared (although in Medscape, the author of the study was quoted as saying that “the pattern was still similar”). A piece of misinformation that reappeared in some of the sources was that the increased risk was similar whether the women had early menopause naturally or because their ovaries had been surgically removed. The research article clearly states that the authors did not have sufficient power (in research this means, basically, enough subjects to get an accurate answer to the question) to determine this.

I was puzzled why so much publicity was given to this study. In my opinion, it did provide some interesting, suggestive results and contributed information about women from a range of ethnic groups (who have been understudied in the past), but the study’s results were modest and inconclusive. However, what the article did do was to claim to support the underlying assumption that menopause and heart disease are related, an idea that keeps re-occurring in the professional literature, even stated as though it is a fact, although the evidence for it has been at the very best arguable and weak. A recent SMCR blog post by Chris Hitchcock analyzed media misreporting of the results of another research project intended to test this relationship. In the study I am discussing, highlighting weak data that seems to suggest a relationship between menopause and ill health, blurring the distinction between natural and surgical menopause, contribute to this meta-message. Ages 40 to 45 would be considered within the normal age range for menopause by many professionals, but is here defined as creating health risks. I would hate to think that meta-messages promoting ideas that menopause is unhealthy and causes risk of heart disease contributed to the perceived importance of the article.

A scientific paper was recently published which looked at how shifting patterns of daily light and darkness affect pregnancy in mice. The authors were interested in this question because studies have suggested that humans who experience such patterns, such as shift workers or women who travel repeatedly across time zones, have reduced fertility. In their study, pregnant mice were divided into three groups. All groups had 12 hours of light followed by 12 hours of darkness. The control group had the same pattern throughout the 21 days of pregnancy. The other two groups had shifting patterns. In one, the 12 hours of light started six hours earlier every five days (phase advanced group); in the other, six hours later (phase delayed group). In the control group, 90% of the mice had successful pregnancies and deliveries; in the phase advanced group, 22%; in the phase delayed group, 50%.

Circadian rhythms is the general term for biological activities that have a 24-hour cycle, like sleeping and waking, or like hormones whose amounts vary during the course of a day. There are many circadian rhythms in humans, animals, and plants.

They are internal, determined by the physiology of the animal or plant. However, they are also entrained (synchronized with) environmental events like the amount of light at night vs. during the day. This entrainment means the rhythms match what is going on in the environment and also can adjust to environmental change. In the pregnant mouse experiment, the light shifts were so large they disrupted the internal circadian timekeeper, which had cascading effects on mouse physiology and success in maintaining a pregnancy.

There are also many physiological rhythms that mesh with environmental patterns on longer or shorter time scales, for reproduction as well as many other aspects of biology. Zucker (1988), for example, found an annual rhythm to whether the amounts of a hormone called luteinizing hormone (LH) had a feedback relationship (that is, interaction) with the amounts of estrogen in ground squirrels. Typically in a mammal, LH increases estrogen production, and then when estrogen levels reach a high point the LH surges which initiates ovulation. For ground squirrels, who only become pregnant during January to March instead of having a regularly repeating cycle throughout the year, this relationship between hormones only exists during the breeding season. If the ovaries of females are surgically removed (so that their bodies don’t make estrogen), LH levels still go up to initiate the breeding season at the correct time of year; that is, levels of LH appear to be controlled by some environmental factor.

There are also social influences on the biology of reproduction in animals. Nelson (1999) summarized some of them: If four or more female mice were housed together in a cage, their cycles occurred less frequently. If they were then exposed to a male, they ovulated at the same time. In a study of albino mice, if a strange male was introduced into the cage of pregnant females, the females spontaneously aborted about 25% of the time. If the male who impregnated the female was re-introduced into the cage, there were no miscarriages. Female rats that were handled daily by researchers reached puberty at an earlier age than did rats who were not, and mice housed alone reached puberty sooner than mice housed with other females.

What does this mean for humans? There are not necessarily direct correspondences between animal and human research. Sometimes human physiology is simply differerent; sometimes, exactly the same. In addition, humans may have many influences where animals have fewer, so big, determining effects in animals may be mere suggestions in humans, one factor among many. On the other hand, the circadian research I discussed above was suggested by the possibility that shift workers and frequent travelers have fertility problems. Many social influences on human menstruation — synchronized menstrual cycles among college roommates, effects of stress — have been reported.

The possibility that intrigues me is this: We are individuals, but we are also intrinsically part of larger environments. Reproductive biology is about our inner organization of hormones, brain chemicals, goals and interests, but it is also about the viability and value of conception in specific social groups and physical environments. Our physiology is inside our skins, internal to us, but is also related to maintaining a state of balance with our physical and social environments.

Photo: Public Domain // LARC birth control methods are highly effective, in part, because women can "forget about them."

On the Coming off the Pill (COTP) MIND MAP GUIDE I proposed in an earlier post in this Coming Off The Pill series, mindful methods dominate the Birth Control branch: condom, spermicide, diaphragm, fertility awareness and copper IUD. Only the latter could be considered forget-about-it birth control. Have it put in, then forget about it.

What got me thinking about this dichotomy is the Contraceptive CHOICE Project, a new study by researchers at Washington University School of Medicine in St. Louis. More than 7500 participants were free to choose, with all costs covered, from a range of contraceptives. (Diaphragms and fertility awareness training were not included.) Contraceptive failure rates over the course of the study were compared for the methods offered. The key result?

“Women who used birth-control pills, the patch or vaginal ring were 20 times more likely to have an unintended pregnancy than those who used longer-acting forms such as an intrauterine device (IUD) or implant.”

The difference in effectiveness was even more profound for women under 21 who used the pill, patch or ring. Their risk for unintended pregnancy with these methods, versus long-acting reversible contraceptives (LARCs), was almost twice as high as for older women.

The reason for the higher failure rates is human error. Women, and especially women under 21 it seems, don’t always remember to take their pills, change their patches, or check to ensure their rings haven’t fallen out. These methods require a certain degree ofmindfulness. The reason that LARCs are more effective, according to senior author Dr. Jeffrey Peipert, is “because women canforget about themafter clinicians put the devices in place.”

There are several things I find troubling about the researchers’ contention that forget-about-it birth control is better just because it’s more effective, and that these methods should be among the first offered to women by clinicians.

Firstly, they fail to acknowledge that many women do not tolerate these “forget-about-them” methods. Among the choices made available to study participants were the contraceptive shot, which I presume was Depo-Provera, and an unspecified hormonal implant. (Implants are slow-release hormonal devices inserted under the skin of a woman’s arm.) Side effects and ongoing problems with such methods abound, and are anything but forgettable. IUDs, both copper and the hormonal Mirena, have fewer drawbacks but they aren’t problem free either. Women experience a range of side effects with the copper IUD. As for the Mirena, some women love it, others hate it.

Secondly, the implication that women under 21 especially should be encouraged (perhaps coerced?) by clinicians to use forget-about-it LARC birth control methods just makes me sad. I get that preventing teen pregnancy is an important public health goal, but the potential for harm to young women’s overall health and psycho-sexual development by the use of such methods, Depo-Provera and contraceptive implants in particular, should be cause for caution and concern.

Maybe it’s time to research mindful birth control methods. Might more women choose barrier and fertility awareness based methods if expert training and support to ensure confident, effective use of these methods were provided free of charge, as were the expensive LARC methods in this study? I guarantee researchers would have no trouble finding women to participate.

As I embark on my 40th year I look ahead to menopause. I guess there is a good chance I’m approaching some foggy years. Brain fog, that is.

In the past week a flurry of online news articles review new research findings on the “brain fog” that many perimenopausal women experience. The brain fog is more easily understood as a slight memory problem, if you take the time to read through the various news stories. A new study analyzed how 75 individual women, aged 40 to 60, rated their memory performance based on factors like how often they forgot details and how serious their forgetfulness was. Researchers also gathered information about the women’s overall health, mood and hormone levels, as well as other menopausal symptoms, and tried to figure out the extent to which this “brain fog” exists. According to news reports, about 41 percent of the women in the study reported having forgetfulness that was “serious,” and those who felt that their memory problems were serious were more likely to score poorly on tests of working memory and attention. Some women who rated their memory problems as serious also reported some depression and other symptoms like hot flashes and sleeping problems. Other researchers suggest that the memory problems women experience are related to changing levels of estrogen in a woman’s body at menopause, but interestingly this new study did not find links to changing hormone levels.

The whole notion of “brain fog” is interesting, and I am suspicious of it as a strictly menopausal symptom. What about the brain fog we all experience when we’re tired or sick or just way too busy? Defining brain fog as a “menopausal” (really, perimenopausal) symptom further defines middle-aged women as somehow less than functional and set them up to be taken less seriously.

Putting this issue aside, though, what I actually find most interesting about all of the news coverage of this study is just how different each report of the study is. I am reminded that we should all be careful of which report we read about a study. For example, the first article I read on this study was placed in the Los Angeles Times and focused on the possible connections between menopausal brain fog, depression, and dementia. I was left feeling like the author of the article inferred that all menopausal women might have depression or dementia and that they should seek treatment. After reading this article I was angry because I felt as if I had been warned that midlife brain fog was the beginning of an inevitable decline for all women. Then I read a WedMD piece that simply described the study and did not concentrate on depression, dementia, or the need for treatment, and I wasn’t really sure what to make of the research study. Finally I read an article by a HealthDay reporter which quoted one of our own, SMCR member Nancy Wood, who reminds readers that “a number of other stressors in life, from work to taking care of children and parents, that pile up around the same time as menopause can hinder memory and ability to concentrate.” In addition, this article’s author states that “memory problems are not necessarily an early sign of dementia” and cognitive ability is regained after other perimenopausal symptoms subside. This third article concluded that the research study is helpful because findings suggest that brain fog is real – that women aren’t crazy – but that it is normal and not that detrimental to women’s long-term cognitive abilities.

Of course, nothing is a substitute for reading the original article published by Miriam Weber and her co-authors this March in the journal, Menopause. But if you need a quick synopsis of what a research study finds just make sure you know its source and think about whether the coverage of the details makes sense! I for one like the tone of the HealthDay news article – that, if brain fog exists, it is temporary and normal and could be caused by lots of things. It is not necessarily an indicator of depression or dementia or even a permanent memory problem. Continue reading...

Guest Post by Harriet Hall, M.D.

When women live together, do their menstrual cycles tend to synchronize? It’s been a long time since I first heard that claim. I didn’t believe it, for a number of reasons. I had never observed it myself, I saw no plausible mechanism to explain how it could happen, I thought the statistics to prove it would be problematic and complicated, and I suspected that confirmation bias and selective memory might have persuaded people that a spurious correlation existed. How often do women say “Oh, look! We’re having our periods at the same time”? How often do they say “Oh, look! We’re having our periods at different times”? Now that many years have passed since my first encounter, I thought it would be fun to revisit the claim and see whether science has supported it or rejected it.

A perusal of PubMed and other Internet sources left me confused and amused.

Synchrony Is Difficult to Define

Consider that the normal menstrual cycle can vary from 21 to 35 days and can last 2 to 7 days. Consider that some women are regular and consistent, while others have variable patterns, even “regularly irregular” patterns. Consider that anovulatory cycles and other conditions often lead to menstrual irregularities that fall outside the normal range. Consider that strenuous exercise and other life events can affect menstruation. Put all that together, and you can see that often cycles will overlap simply by chance, and that it is difficult to define synchrony.

If two women have regular 28 day cycles and 7 day periods, the maximum number of days they could not overlap is 14. On average, their periods will be 7 days apart, and half the time they will be closer.

How could a 21 day cycle ever “synchronize” with a 35 day cycle? For example if you compare a woman with a regular 35 day cycle who starts on January 1 to a woman with a 21 day cycle who starts two weeks later on January 15, their next periods will coincide almost perfectly (Feb 4-10 and Feb 5-11) but they will diverge after that. Would it count if the last day of one woman’s period overlapped with the first day of another woman’s? What if half the periods coincide and half don’t? The whole thing is problematic.

What Does the Literature Say?

It all started with Martha McClintock. In a paper published in Nature in 1971 she found that “social interaction” in a college dormitory setting could have a strong effect on the menstrual cycle. A follow-up study in 1998 tended to support the hypothesis that pheromones were involved: smelling armpit secretions of other women could either lengthen or shorten cycles depending on what part of her cycle the donor was in.

I’ll summarize rather than trying to cover everything published on the subject. A Scientific American article did a good job of reviewing the literature as of 2007. Suffice it to say that about half the published papers support the synchronization hypothesis and half don’t; and the half that do have been harshly criticized for their poor design and poor statistical analyses. So we haven’t reached a consensus, but it’s looking more likely that synchronization is a myth.

A study in a nursing journal assumes that synchronization occurs and addresses the subjective meaning of the experience to

assist nurses to understand the holistic aspects of this everyday experience of women and to design effective strategies and techniques to help women gain knowledge about their cycle functions, promote healthy attitudes toward menstruation as a process, and acknowledge and honor this natural, healthy aspect of their menstrual cycle.

I will be kind to those nurses and apply Thumper’s rule. (In Bambi, he said “If you can’t say something nice, don’t say nothing at all.”)

Dr. Robert Brenner, who is the lead researcher conducting these studies in the Division of Reproductive Sciences at Oregon Regional Primate Research Center, notes that this has potential beyond just a new lifestyle drug:

I would emphasize that we are not talking here only about lifestyle choices but also about the potential to bring relief to the many women who suffer years of misery from distressing complaints such as endometriosis, and painful and excessive monthly bleeding. In fact, excessive bleeding is one of the major reasons that women undergo hysterectomy, and this treatment may also reduce the need for this surgical procedure, with all its attendant risks and costs.